By the year 2030, 20% of the US population is expected to be over 65 years old. As life expectancy rises in the US, the incidence of aging-related diseases is also rising. Although neither the genes involved in human aging nor the biochemical roles of their gene products are known, there is a preponderance of data from studies in nematodes and preliminary results from other model systems that suggest that mutations conferring increased stress resistance lead to longer-lived, more robust organisms. While previously identified nematode gerontogenes negatively regulate stress resistance, a novel nematode gerontogene was recently identified that is a positive regulator of stress resistance. In Phase l research, GenoPlex will seek nematode and mammalian homologues of this stress resistance gene and will determine if it is part of a gene family. We will determine if overexpression in transgenic nematodes of the nematode or mammalian genes we identify results in increased life expectancy, enhanced stress resistance, and delayed appearance of signs of aging. If successful, Phase 11 will focus on developing transgenic mice that overexpress the genes identified in Phase l. The transgenic mice will then be used in studies to validate the genes as targets for pharmacologic intervention to postpone or even prevent aging-related diseases. Additionally, alleles or mutations of the validated genes that correlate with early onset of aging- related diseases will be identified. PROPOSED COMMERCIAL APPLICATION: The commercial application of this research is to identify and validate biological targets for new therapeutics that might postpone or even prevent aging-related diseases. Additionally, the correlation of alleles or mutations with early onset of aging-related diseases will be the basis for developing diagnostic tests that will identify individuals who would benefit from therapeutic intervention.